Autonomic dysreflexia is a potentially life-threatening medical emergency occurring in patients with spinal cord injury (SCI) above the midthoracic level. The most prominent symptom is severe paroxysmal hypertension induced by a weak trigger stimulus arising from below injury level (often from the bladder or colon). Intracranial hemorrhage, seizures, and retinal detachment may occur in response to the severe hypertension, while the less severe manifestations seriously degrade patients' quality of life. Current therapy is generally limited to avoiding or removing trigger stimuli and emergency room treatment. Better therapy is needed to keep patients out of the emergency room and improve their quality of life, and we propose such therapy based on chronic inhibition of spinal sympathetic reflexes. The spinal sympathetic reflexes are strongly inhibited in intact spinal cords by descending brainstem pathways that tonically release the neurotransmitters norepinephrine, serotonin and GABA, which for the sake of brevity are henceforth, termed descending neurotransmitters. This tonic inhibition is lost with complete SCI and never restored, leaving the reflexes uninhibited. In consequence, activation of spinal sympathetic reflexes can evoke markedly elevated sympathetic outflow from spinal cord segments controlling the high-volume splanchnic circulation, resulting in the hypertension of autonomic dysreflexia. Our novel overall hypothesis is that autonomic dysreflexia can be suppressed by chronically restoring tonic inhibition with either nonselective agonists (the descending neurotransmitters) or receptor subtype- selective agonists. Our clinically significant goal is to provide proof of concept for suppression of autonomic dysreflexia by agonist delivery using technology already employed in humans for other indications: the implantation of pumps with intrathecal catheters. We will determine the ability of intrathecally delivered agonists to suppress autonomic dysreflexia provoked by visceral distension in rats four weeks after T4 spinal cord transection, as well as their effect on orthostatic hypotension. Specific aim 1 does so for acute intrathecal delivery of both nonselective and selective agonists to the T6 spinal cord segment. The dose-response curve and half-life for each agonist will be used to select initial doses for Specific aim 2. Fos expression will be used to determine if effects are due to afferent or efferent inhibition. Specifi aim 2 will determine the ability of chronic intrathecal delivery of the agonists to suppress autonomic dysreflexia using catheters connected to programmable pumps implanted 4 wk post-SCI and used for a period of at least 7 weeks. Favorable results from the proposed studies will pave the way for clinical trials in the very near future. They may additionally lay the foundation for investigation of descending neurotransmitter delivery by intraspinal neuronal grafts. PUBLIC HEALTH RELEVANCE: A quarter-million people in the US have spinal cord injury (SCI), another 11,000 sustaining SCI every year. Some 50-75% of people with SCI above the midthoracic level have autonomic dysreflexia, which is large and potentially life-threatening increases in blood pressure in response to relatively minor stimulation, often from the urinary bladder and colon. Our goal is to provide proof of concept for the use of chronic intraspinal drug therapy to treat patients with autonomic dysreflexia in the near future.